1. Field of the Invention
This invention is directed to novel bicyclic compounds, to the uses of these compounds in various medicinal applications, including treating disorders amenable to treatment by peptide deformylase inhibitors such as treatment of bacterial infections, and to pharmaceutical compositions comprising of these compounds.
2. Background
Treatment of microbial infection in host organisms requires an effective means to kill the microbe while doing as little harm to the host as possible. Accordingly, agents that target characteristics unique to a pathology-causing microorganism are desirable for treatment. Penicillin is an extremely well known example of such an agent. Penicillin acts by inhibiting biosynthesis of bacterial cell walls. Since mammalian cells do not require cell walls for survival, administration of penicillin to a human infected with bacteria may kill the bacteria without killing human cells. However, the use of antibiotics and antimicrobials has also resulted in increased resistance to these agents. As bacteria become resistant to older, more widely used antimicrobial agents, new antimicrobials must be developed in order to provide effective treatments for human and non-human animals suffering from microbial infection.
Peptide deformylase is a metallopeptidase found in prokaryotic organisms such as bacteria. Protein synthesis in prokaryotic organisms begins with N-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by the enzyme peptide deformylase (PDF); this activity is essential for maturation of proteins. It has been shown that PDF is required for bacterial growth (Chang et al., J. Bacteriol., Vol. 171, pp. 4071-4072 (1989); Meinnel et al., J. Bacteriol., Vol. 176, No. 23, pp. 7387-7390 (1994); Mazel et al., EMBO J., Vol. 13, No. 4, pp. 914-23 (1994)). Since protein synthesis in eukaryotic organisms does not depend on fMet for initiation, agents that inhibit PDF are attractive candidates for development of new antimicrobial and antibacterial drugs. Prokaryotic organisms, including disease-causing prokaryotes, are described in Balows A, Truper H G, Dworkin M, Harder W and Schleifer K-H (eds.), “The Prokaryotes”, 2nd ed., New York: Springer-Verlag Q. (1992); and Holt J G (Editor-in-chief), “Bergey & Apos, S., Manual of Systematic Bacteriology”, Vols. 1-4, Baltimore: Williams & Wilkins (1982, 1986, 1989).
PDF is part of the metalloproteinase superfamily. While PDF shares many of the features that characterize metalloproteinases, PDF differs from other members of the superfamily in its secondary/tertiary structure and the metal ions that are coordinated in the active site. Metalloproteinases are critical to many aspects of normal metabolism. The class known as matrix metalloproteinases (MMPs) are involved in tissue remodeling, such as degradation of the extracellular matrix. These enzymes are believed to play a role in normal or beneficial biological events such as the formation of the corpus luteum during pregnancy (see Liu et al., Endocrinology, Vol. 140, No. 11, pp. 5330-5338 (1999)), wound healing (Yamagiwa et al., Bone, Vol. 25, No. 2, pp. 197-203 (1999)), and bone growth in healthy children (Bord et al., Bone, Vol. 23, No. 1, pp. 7-12 (1998)). Disorders involving metalloproteinases have been implicated in several diseases such as cancer, arthritis and autoimmune diseases. Because of the importance of MMPs in normal physiological processes, it would be preferable to develop agents that inhibit PDF, a metalloproteinase present only in prokaryotes, while avoiding significant inhibition of MMPs. Alternatively, PDF inhibitors that also inhibit MMPs may be of use where the therapeutic benefits of inhibiting PDF outweighs the risk of side effects from MMP inhibition.
While a wide variety of compounds have been developed as candidate inhibitors of MMPs and other metalloproteinases, research on inhibitors of PDF is much less extensive. In view of the importance of identifying new antibiotics to treat bacteria resistant to existing antibiotics, it is desirable to develop novel inhibitors of PDF for evaluation and use as antibacterial and antimicrobial agents. The present invention fulfills this need.